WO2006118210A1 - Procede de prevention de la degradation d'un compose dihydropyridine - Google Patents

Procede de prevention de la degradation d'un compose dihydropyridine Download PDF

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Publication number
WO2006118210A1
WO2006118210A1 PCT/JP2006/308869 JP2006308869W WO2006118210A1 WO 2006118210 A1 WO2006118210 A1 WO 2006118210A1 JP 2006308869 W JP2006308869 W JP 2006308869W WO 2006118210 A1 WO2006118210 A1 WO 2006118210A1
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WO
WIPO (PCT)
Prior art keywords
wet
compound
dihydropyridine compound
dihydropyridine
amlodipine besylate
Prior art date
Application number
PCT/JP2006/308869
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English (en)
Japanese (ja)
Inventor
Toshio Suzuki
Original Assignee
Eisai R & D Management Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eisai R & D Management Co., Ltd. filed Critical Eisai R & D Management Co., Ltd.
Priority to US11/919,232 priority Critical patent/US20100016378A1/en
Priority to JP2007514815A priority patent/JP5103173B2/ja
Publication of WO2006118210A1 publication Critical patent/WO2006118210A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to a method for stabilizing a dihydropyridine compound, and more specifically, a method for preventing the formation of a hydrate of a dihydropyridine compound when a dihydropyridine compound is wet-treated, and a dihydropyridine compound.
  • the present invention relates to a pharmaceutical composition obtained by wet processing.
  • Tablets are frequently used as pharmaceutical dosage forms because of their convenience and dosage.
  • Patent Document 2 discloses a pharmaceutical composition as a corresponding method. A tablet obtained by a direct tableting method, in which crystalline cellulose is blended at a high concentration of 87-94%, is disclosed.
  • Patent Document 1 a tablet containing a dihydropyridine compound is obtained by a direct tableting method, but this direct tableting method is excellent in that the process is simple. Since it is mixed in a powdered state, when a dihydropyridine compound component having poor fluidity such as amlodipine besylate is used, there is a problem that it is difficult to mix uniformly.
  • Patent Document 1 JP-A-10-298062
  • Patent Document 2 International Publication No. 03Z051364
  • the object of the present invention is to ensure the stability of the dihydropyridine compound in the pharmaceutical composition obtained in the step of adding water (wet treatment step) such as wet kneading, wet granulation, fluidized bed granulation and the like. And a pharmaceutical composition with improved stability of the dihydropyridine compound obtained by the method, and a pharmaceutical composition containing the dihydropyridine compound that is superior in dosage and convenience using the composition. It is to be.
  • the inventors of the present invention have conducted extensive studies to solve the above-mentioned problems, and as a result, obtained by wet-treating a dihydric pyridine-based compound with a cellulose-based polymer substituted with a methyl group. It was found that the stability of the dihydropyridine compound in the pharmaceutical composition obtained by the treatment was significantly improved. In addition, the inventors have found that the above method suppresses the formation of hydrate crystals and amorphous forms of dihydropyridine compounds and the subsequent decomposition into pyridine compounds, leading to the present invention.
  • the present invention is a method for stabilizing a dihydric pyridine compound, characterized in that the dihydropyridine compound is wet-treated with a cellulose polymer substituted with a methyl group, and the dihydropyridine compound is substituted with a methyl group.
  • a method of preventing formation of a hydrate of a dihydropyridine compound and decomposition of Z or a dihydropyridine compound, characterized by wet-treating a cellulosic polymer, and cellulose in which a dihydropyridine compound is substituted with a methyl group The present invention relates to a pharmaceutical composition and the like obtained by wet treatment with a polymer and having improved stability of a dihydropyridine compound. The invention's effect
  • the formation of unstable hydrates can be prevented in a pharmaceutical composition containing a dihydropyridine compound
  • water is used as in the direct tableting method and the dry granulation method. Kneading with water is possible only with a manufacturing method that is not used, and furthermore, it is possible to manufacture by a wet granulation method, which is a general manufacturing method. Furthermore, using these methods, it is possible to provide a pharmaceutical composition that can ensure the stability of the dihydropyridine compound.
  • the dihydropyridine-based compound that can be used in the present invention refers to a compound having a dihydropyridine skeleton. Power that can mention I prefer to use lopipine.
  • amlodipine can be used in the form of various salts in addition to the free form.
  • amlodipine when “amlodipine” is simply described, it means any of a free form and various salts formed, except where the salt is clearly indicated.
  • amlodipine it is preferable to use ambuchi dipine besylate, which is a compound represented by the following chemical formula. Amlodipine besylate can be obtained from Dr. Reddy, s.
  • Examples of the cellulosic polymer substituted with a methyl group that can be used in the present invention include methylcellulose and hydroxypropylmethylcellulose.
  • the methyl cellulose that can be used in the present invention can be classified into various grades depending on the difference in viscosity.
  • any grade may be used.
  • Metrols manufactured by Shin-Etsu Chemical Co., Ltd.
  • Methocel A manufactured by Dow Chemical Co., Ltd.
  • Marporose manufactured by Matsumoto Yushi Seiyaku Co., Ltd.
  • hydroxypropyl methylcellulose that can be used in the present invention is different in the degree of substitution of methyl groups, the degree of substitution of hydroxypropyl groups, and the viscosity.
  • hydroxypropylmethylcellulose for example, Metroze 65SH (manufactured by Shin-Etsu Chemical Co., Ltd.), Methocel K (manufactured by Dow Chemical Co., Ltd.) and the like are commercially available, and these can be used.
  • the method for adding a cellulose polymer substituted with a methyl group in wet kneading and wet granulation is not particularly limited, and for example, a solution containing water Cellulosic polymers substituted with methyl groups may be dissolved or suspended in the solution, and then the solution or suspension may be added. Cellulose polymers substituted with methyl groups Although it may be added as a powder, it is preferable to add after dissolving the cellulose polymer substituted with methyl groups in water.
  • the amount of the cellulose-based polymer substituted with a methyl group used in the present invention varies depending on the process used, dosage form, etc., but is usually a dihydropyridine compound (when a salt is formed). Is based on the weight including salt). For example, 0.0005 05 parts by weight or more of 1 part by weight is sufficient. Of these, 0.0005 part by weight or more is preferable, and 0.0005 part by weight or more is more preferable.
  • wet treatment means that a dihydropyridine compound is treated in a water-containing state, and is not limited to a specific treatment.
  • wet treatment include, for example, wet kneading in which a solution containing a cellulose compound substituted with a methyl group is added to a powder containing a dihydropyridine compound, kneading the mixture, and then wet granulation.
  • wet granulation and fluidized bed granulation in which a solution containing a cellulose compound substituted with a methyl group is sprayed on a powder containing a dihydropyridine compound and sprayed with a spray.
  • the wet granulation method a mixing and stirring granulation method using a planetary mixer or a screw type mixer, a high speed mixing and stirring granulation method using a Henschel mixer or a super mixer, a cylindrical granulator, a rotary type granulation method Machine, screw extrusion granulator
  • the present invention can be subdivided into methods such as extrusion granulation using a pellet mill type granulator, rolling granulation, fluidized bed granulation, spray granulation, etc. You can use it in any way.
  • the water used in the wet treatment in the present invention is not particularly limited, but it is preferable to use purified water which is usually used in the production of pharmaceutical products and the like.
  • purified water which is usually used in the production of pharmaceutical products and the like.
  • it may be added as a mixed solvent in which an organic solvent such as alcohol is mixed with water.
  • water hydrophilic solvent
  • water hydrophilic solvent
  • the pharmaceutical composition of the present invention is not limited to the form as long as it is a pharmaceutical composition obtained as a result of wet processing.
  • a pharmaceutical composition obtained as a result of wet processing for example,
  • Amlodipine besylate (manufactured by Dr. Redds) 3.5 g of mantol (manufactured by Towa Kasei Kogyo Co., Ltd.) 60 g was mixed and mixed with Mechanomyl (manufactured by Okada Seiko). 2. 9% methyl Kneading was performed using 8.95 g of an aqueous solution of roulose (trade name Metrows 25, manufactured by Shin-Etsu Chemical Co., Ltd.). After kneading, fluidized bed drying was performed with a Flow Coater (FreundZOkawara) at an intake air temperature of 90 ° C. Sieving with a sieve gave granules.
  • amlodipine besylate and mannitol (yellow ferric trioxide (genuine chemistry)) were mixed with mechanomyl, and an aqueous solution containing methylcellulose or polypyrrolidone (ISP) , Hereinafter referred to as “PVP”), or kneaded with an aqueous ethanol solution containing polybulualcohol (Japanese fat and oil, hereinafter referred to as “PVA”).
  • PVP methylcellulose or polypyrrolidone
  • PVA aqueous ethanol solution containing polybulualcohol
  • the obtained wet powder was tableted and dried using an EMP quick-disintegrating tableting system (apparatus disclosed in Japanese Patent No. 3179658) to obtain fast-disintegrating tablets. Diameter 8mn! ⁇ 8.5mm, thickness 3. 2mn! ⁇ 3.4mm, molding pressure was 15kgf, drying temperature was 90 ° C.
  • Example 4 Example 5
  • Example 6 Example 7
  • Example 9 Amlodipine besinoleate 10.4g 10.4g 10.4g 10.4g Mannol 28L lg 281.lg 281 lg 281. lg 281. lg 281. lg 281. lg methinorescenellose 0.072g 0. 36g 0. 72g 0. 96g 1. 2g 1. 44g yellow ferric oxide 8.5g 8. 5g 8. 5g 8.5g 8 .5g 8.5g
  • Example 2 and Example 3 To the granules obtained in Example 1, Example 2 and Example 3, Avicel PH101 or Avicel 1 3 111017 Mann-toll 1 3 (weight ratio 4: 6 mixture) was mixed with the composition shown in Table 4. After weighing into a bag and mixing well in a plastic bag, it was molded with Shimadzu Autograph AGS-1000D at a tableting pressure of 300 kgf to obtain about 180 mg of a tablet containing 5 mg or 2.5 mg as an active ingredient. The mortar and pestle were 8mm, and the mortar and pestle were coated with magnesium stearate and tableted.
  • Methylcellulose (Shin-Etsu Chemical Metrose SM-25)
  • Methylcellulose (Shin-Etsu Chemical Metrose SM-4)
  • a stability test (acceleration test) of amlodipine besylate was carried out using the granules, tablets and the like obtained in the above-mentioned Examples and Comparative Examples. Abuse conditions, and in these trials, The purity and crystal form were measured according to the following procedure.
  • a transparent glass bottle (sealed or opened) or a petri dish was used as the storage container. In the petri dish, the specimens were spread evenly.
  • a constant temperature and humidity chamber under the following conditions was used. 40 ° C 75% relative humidity (hereinafter referred to as R.H.): Trade name FX230p (ETAC), 60 ° C: Trade name DN94 (YAMATO).
  • the measurement of the impurity content in the pharmaceutical composition containing amlodipine besylate was evaluated by concentration gradient control (gradient method) of liquid chromatography described in JP. The numerical value was calculated by the area percentage method (relative area method).
  • the liquid chromatograph (hereinafter referred to as HPLC) was Hitachi D-7000, and the measurement was performed under the following conditions.
  • Detector UV absorptiometer (measurement wavelength: 241 nm), column: Inerts il ODS— 2 4.6 mmX 15 cm, particle size 5 m, column temperature: 40 ° C, flow rate: 0.9 mL / min, Injection volume: 10 L, analysis time: 45 minutes, HPLC mobile phase A: Acetonitrile Z water ZHC1 04 (100: 90 0: 1), HPLC mobile phase B: acetonitrile / water / HC104 (900: 100: 1) ), The gradient program followed Table 9.
  • ⁇ Preparation of sample solution> The sample was weighed and dissolved by adding a 30% acetonitrile solution to prepare a drug substance mass of 0.7 mg / mL. If necessary, centrifugation (3000 rpm, lOmin.) And filter filtration (excluding the initial fraction of 4 mL) were used as the sample solution.
  • the crystal form of the pharmaceutical composition containing amlodipine besylate was evaluated by differential scanning calorimetry (DSC) of the thermal analysis method described in JP.
  • the instrument was DSC3100S (Mac Science), and the temperature was measured from room temperature to 210 ° C at a heating rate of 5 ° CZmin. Or 10 ° CZmin.
  • the sample was weighed in an aluminum container and sealed.
  • the reference material used as a control was an empty sealed aluminum container.
  • Anhydrous crystals of amlodipine besylate do not undergo crystal transition until the decomposition point near 200 ° C.
  • the monohydrate crystal and dihydrate crystal have an endothermic peak accompanying water desorption at room temperature to 100 ° C, and an exothermic peak accompanying crystal transition to an anhydrous crystal at 120 ° C or higher. Each is observed.
  • Example 13 were more stable than the granules obtained in Comparative Example 1 under any conditions. Further, the crystal form after production of the granules obtained in Example 1 and Comparative Example 1 was measured. As a result, in Example 1 granulated with methylcellulose, amlodipine besylate was an anhydrous crystal, and in Example 1 granulated without using methylcellulose, amlodipine besylate was amorphous. .
  • Example 49 The tablets obtained in Example 49 and Comparative Examples 3 and 4 were subjected to the same stability test as in Test Example 1 above. The results are shown in Table 11.
  • Example 49 The crystal form of amlodipine contained in the tablets obtained in Example 49 and Comparative Example 3 was measured.
  • the amlodipine besylate in the tablet coexisting with methylcellulose during wet kneading (Example 49) is an anhydrous crystal
  • the tablet coexisting with PVP during wet kneading (Comparative Example 3) The amlodipine besylate was found to be a hydrate crystal.
  • Crystal form Comparative example 8 (control) Hydrate crystal Example 12-1 Anhydrous crystal Example 12 _ 2 Anhydrous crystal Example 13-1 Anhydrous crystal Example 13-2 Anhydrous crystal Example 13-3 Anhydrous Example 14— 1 Anhydrous crystal Example 14 _ 2 Anhydrous crystal [0051] From the above results, it can be understood that when the crystal form is an anhydride, no decomposition product is generated.
  • the present invention can be used for the production of a pharmaceutical composition containing a dihydropyridine compound.

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • Veterinary Medicine (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Hydrogenated Pyridines (AREA)

Abstract

Selon la présente invention, lors de l'ajout d'eau, un composé dihydropyridine tel que l'amlodipine subi une dégradation accélérée en composés de pyridine, soit directement, soit via la formation d'un hydrate instable. Par conséquent, les procédés de fabrication de compositions médicinales contenant des composés dihydropyridine sont limités à ceux ne comprenant pas d'ajout d'eau, comme, par exemple, un procédé d'ajout d'un composé dihydropyridine sous la forme de poudre. Ces procédés ne sont pas adaptés à un système de granulation humide, dans lequel les propriétés de moulage, de dureté, de désintégration, etc. des comprimés peuvent être facilement contrôlées, et l'uniformité des composants peut facilement être assurée en modifiant les conditions de granulation. Lors d'un traitement par voie humide, un composé dihydropyridine est mis en présence d'un polymère à base de cellulose méthylée, de manière à empêcher la formation de l’hydrate du composé dihydropyridine et/ou empêcher la dégradation du composé dihydropyridine.
PCT/JP2006/308869 2005-04-28 2006-04-27 Procede de prevention de la degradation d'un compose dihydropyridine WO2006118210A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US11/919,232 US20100016378A1 (en) 2005-04-28 2006-04-27 Method of preventing dihydropyridine compound from degradation
JP2007514815A JP5103173B2 (ja) 2005-04-28 2006-04-27 ジヒドロピリジン系化合物の分解を防止する方法

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JP2005131906 2005-04-28
JP2005-131906 2005-04-28

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Cited By (8)

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WO2008062435A3 (fr) * 2006-08-15 2008-07-31 Alkem Lab Ltd Formes galéniques stabilisées de bésylate d'amlodipine
WO2010014727A1 (fr) * 2008-08-01 2010-02-04 The Medicines Company Compositions pharmaceutiques, et procédés pour produire de faibles concentrations d'impureté de celles-ci
WO2010107081A1 (fr) * 2009-03-19 2010-09-23 第一三共株式会社 Préparations solide stablement conservée dans un emballage
JP2011207873A (ja) * 2010-03-10 2011-10-20 Dainippon Sumitomo Pharma Co Ltd イルベサルタンとアムロジピンまたはその塩を含有する医薬組成物
JP2013075893A (ja) * 2011-09-13 2013-04-25 Dainippon Sumitomo Pharma Co Ltd イルベサルタンとアムロジピンまたはその塩を含有する安定化された医薬組成物
JP2013525455A (ja) * 2010-04-30 2013-06-20 ブリストル−マイヤーズ スクイブ カンパニー Ｎ−（４−（２−アミノ−３−クロロピリジン−４−イルオキシ）−３−フルオロフェニル）−４−エトキシ−１−（４−フルオロフェニル）−２−オキソ−１，２−ジヒドロピリジン−３−カルボキサミドを含有する医薬組成物
JP2017082006A (ja) * 2007-03-13 2017-05-18 大日本住友製薬株式会社 口腔内崩壊錠
WO2021230308A1 (fr) 2020-05-15 2021-11-18 塩野義製薬株式会社 Composition de médicament à production d'impuretés inhibée

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US10350171B2 (en) 2017-07-06 2019-07-16 Dexcel Ltd. Celecoxib and amlodipine formulation and method of making the same
JP7145121B2 (ja) * 2019-05-31 2022-09-30 信越化学工業株式会社 錠剤の製造方法

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